Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes.

Chloroquine (CQ) is a first-choice drug against malaria and autoimmune diseases. It has been co-administered with zinc against SARS-CoV-2 and soon dismissed because of safety issues. The structural features of Zn-CQ complexes and the effect of CQ on zinc distribution in cells are poorly known. In this study, state-of-the-art computations combined with experiments were leveraged to solve the structural determinants of zinc-CQ interactions in solution and the solid state. NMR, ESI-MS, and X-ray absorption and diffraction methods were combined with ab initio molecular dynamics calculations to address the kinetic lability of this complex. Within the physiological pH range, CQ binds Zn 2+ through the quinoline ring nitrogen, forming [Zn(CQH)Cl x (H 2 O) 3- x ] (3+)- x ( x = 0, 1, 2, and 3) tetrahedral complexes. The Zn(CQH)Cl 3 species is stable at neutral pH and at high chloride concentrations typical of the extracellular medium, but metal coordination is lost at a moderately low pH as in the lysosomal lumen. The pentacoordinate complex [Zn(CQH)(H 2 O) 4 ] 3+ may exist in the absence of chloride. This in vitro / in silico approach can be extended to other metal-targeting drugs and bioinorganic systems.